RU2167657C2 - Pharmaceutical composition for treatment of patients with allergic diseases, method of antihistamine treatment, use of composition for drug preparing - Google Patents

Abstract

FIELD: medicine, pharmacy. SUBSTANCE: invention proposes pharmaceutical composition containing terfenadine metabolite used for treatment of patients with allergic rhinitis. EFFECT: broadened arsenal of agents of indicated prescription. 20 cl, 4 tbl, 5 ex

Description

 The present invention relates to new pharmaceutical compositions containing 4- [1-hydroxy-4- (4-hydroxydiphenylmethyl-1-piperidinyl) butyl] -α, α-dimethylbenzeneacetates and 1- [p- (2-hydroxymethylprop-2-yl) -phenyl] -4- [4- (α-hydroxy-α-phenylbenzyl) piperidin-1-yl] butanol, and their optically pure derivatives. These compositions have a strong antihistamine activity and are suitable for the treatment of allergic rhinitis, asthma and other allergic diseases, without causing side effects associated with the administration of other α-aryl-4-substituted derivatives of piperidinoalkanols, such as terfenadine, including cardiac arrhythmia, drowsiness, nausea, fatigue, weakness and headache, and not only them. In addition, such compositions in combination with non-steroidal anti-inflammatory drugs or other non-narcotic analgesics are suitable for the treatment of coughs, colds, symptoms and malaise, such as colds and / or flu, and general malaise associated with these conditions. The above combinations may optionally include one or more other active ingredients, including decongestants, cough suppressants or cough suppressants, or expectorants.

 In addition, such new pharmaceutical compositions containing 4- [1-hydroxy-4- (4-hydroxydiphenylmethyl-1-piperidinyl) butyl] -α, α, dimethylbenzene acetates and 1- [p- (2-hydroxymethylprop-2-yl ) phenyl] -4- [4- (α-hydroxy-α-phenylbenzyl) -1-piperidin-1-yl] butanol, and their optically pure derivatives, are suitable for the treatment of motion sickness, dizziness, diabetic retinopathy, diabetes complications small vessels and other such conditions that can be correlated with the activity of these derivatives as histamine H-1 receptor antagonists are not challenging at the same time, side effects associated with the introduction of other α-aryl-4-substituted derivatives of piperidinoalkanols, such as terfenadine.

 Also disclosed are methods of treating the above conditions in humans, avoiding the side effects that are associated with the introduction of other α-aryl-4-substituted derivatives of piperidinoalkanols, such as terfenadine, by the introduction of the above pharmaceutical compositions containing 4- [1-hydroxy-4 - (4-hydroxydiphenylmethyl-1-piperidinyl) butyl] -α, α-dimethylbenzeneacetates and 1- [p- (2-hydroxymethylprop-2-yl) phenyl] -4- [4- (α-hydroxy-α-phenylbenzyl ) piperidin-1-yl] -butanol or their optically pure isomers, to the aforementioned person.

 The active compounds in these compositions and methods are metabolic derivatives of terfenadine. From a chemical point of view, these derivatives are methyl-4- [1-hydroxy-4- (4-hydroxydiphenylmethyl-1-piperidinyl) butyl] -α, α-dimethylbenzene acetate, 4- [1-hydroxy-4- (4 -hydroxydiphenylmethyl-1-piperidinyl) butyl] -α, α-dimethylbenzeneacetic acid and 1- [p- (2-hydroxymethylprop-2-yl) phenyl] -4- [4- (α-hydroxy-α-phenylbenzyl) piperidine- 1-yl] butanol and optical isomers of the compounds. These compounds are described by Garteig et al., Argeneimittel-Forchung / Drug Research, 32: 1185-1190 (1982). From a chemical point of view, the optical isomers of these compounds are methyl R - (+) - 4- [1-hydroxy-4- (4-hydroxydiphenylmethyl-1-piperidinyl) butyl] -α, α-dimethylbenzene acetate, methyl-S- (-) - 4- [1-hydroxy-4- (4-hydroxydiphenylmethyl-1-piperidinyl) butyl] -α, α-dimethylbenzene acetate, R - (+) - 4- [1-hydroxy-4- (4-hydroxydiphenylmethyl -1-piperidinyl) butyl] -α, α-dimethylbenzeneacetic acid, S - (-) - 4- [1-hydroxy-4- (4-hydroxydiphenylmethyl-1-piperidinyl) butyl] -α, α-dimethylbenzeneacetic acid, R - (+) - 1- [p- (2-hydroxymethyl-2-prop-2-yl) phenyl] -4- [4- (α-hydroxy-α-phenylbenzyl) piperidin-1-yl] butanol and S - (-) - 1- [p- (2-hydroxymethylprop-2-yl) phenyl] -4- [4- (α-hydroxy-α-phenylbenzyl) piperidin-1-yl] butanol.

или (+) и (-) используются для обозначения направления вращения соединением плоскополяризованного света, причем (-) или

означает, что соединение является левовращающим. Соединение с префиксом (+) или

является правовращающим. При данном химическом строении соединения, называемые стереоизомерами, являются идентичными, за исключением того, что они являются зеркальными изображениями одно другого. Определенный стереоизомер также может быть назван энантиомером, и смесь таких изомеров часто называют энантиомерной или рацемической смесью.Spatial relationships and drug action
Many organic compounds exist in optically active forms, i.e., they have the ability to rotate the plane of plane-polarized light. When describing an optically active compound, the prefixes D and L or R and S are used to ensure the absolute configuration of the molecule near its chiral center (s). Prefixes

or (+) and (-) are used to indicate the direction of rotation of a compound of plane-polarized light, wherein (-) or

means the compound is levorotatory. Connection prefixed with (+) or

is dextrorotatory. With this chemical structure, the compounds called stereoisomers are identical, except that they are mirror images of one another. A particular stereoisomer may also be called an enantiomer, and a mixture of such isomers is often called an enantiomeric or racemic mixture.

 Stereochemical purity can be significant in the pharmaceutical field, when 12 of the 20 most commonly prescribed drugs show chirality. A striking example is the L-form of β-adrenergic blocking agent propranolol, which is known to be 100 times more potent than the D-enantiomer.

 Moreover, optical purity can make a difference, since some isomers may actually be more harmful than just inert. For example, it is indicated that the thalidomide D-enantiomer is a safe and effective sedative when prescribed to combat nausea during pregnancy, while the corresponding L-enantiomer is considered a potent teratogen.

 The enantiomers of 4- [1-hydroxy-4- (4-hydroxydiphenylmethyl-1-piperidinyl) butyl] -α, α-dimethylbenzeneacetic acid are described in Zamani et al ,, Chirality, 3: 467-470 (1991). This work indicates that the (R) enantiomer of orally administered racemic terfenadine is predominantly oxidized in rats to form a carboxylic acid metabolite enriched in the (R) enantiomer. Enantiomers of 4- [1-hydroxy-4- (4-hydroxydiphenylmethyl-1-piperidinyl) butyl] -α, α-dimethylbenzeneacetic acid are also described by Chan et al, J. Chromatog, 571: 291-297 (1991). This work indicates that terfenadine in the human body does not undergo any stereoselective isomeric interconversion.

 Terfenadine is an antagonist of the histamine receptor H-1 protein. Histamine receptor proteins are found in tissues in two well-recognized forms - in the form of H-1 and H-2 receptors. H-1 receptors are receptors that mediate the antagonistic response to conventional antihistamines. H-1 receptors / H-1 receptors / are present in the ileum of the guinea pig, in the skin of rhesus monkeys and in the bronchial smooth muscle of guinea pig. Terfenadine inhibits the action of histamine in the isolated ileum of the guinea pig, inhibits the appearance of blisters on the skin of rhesus monkeys caused by histamine and protects the guinea pig from the lethal outcome caused by histamine.

 Through reactions mediated by the H-2 receptor, histamine stimulates the secretion of gastric juice in guinea pigs and the chronotropic effect in the isolated atria of guinea pigs. Terfenadine has no effect on the secretion of gastric juice caused by histamine and does not alter the chronotropic effect of histamine on the atrium. Thus, terfenadine does not have a clear effect on the histamine H-2 receptor. See Cheng et al., Drug Development Research, 2; 181-196 (1982).

 Terfenadine is well absorbed, but during the metabolism it is comprehensively converted. See Okerholm et al., Biopharmaceuties and Drug Distribution, 2: 185-190 (1981). Two major metabolites have been identified, and it is believed that one of the metabolites -4- [1-hydroxy-4- [4- (hydroxydiphenylmethyl-1-piperidinyl) butyl] -α, α-dimethylbenzeneacetic acid - may exhibit antihistamine activity in vitro, but Actual data not published. See Garteig et al. Argneimittel-Forschung / Drug Research 32: 1185-1190 (1982).

 Based on the antihistamine activity of terfenadine, researchers evaluated the effects of terfenadine in the treatment of allergic rhinitis. Clinical testing of the effectiveness of terfenadine has shown that it is slightly less effective than chlorpheniramine, another N-1 antagonist. See Connell, Pharmacetherapy, 5: 201-208 (1985).

Terfenadine has also been suggested to be useful in treating asthma. Terfenadine suppresses the increase in airway resistance caused by LTD ₄ (leukotriene D ₄ ) in guinea pigs. See Akagi et al., Oyo yakuri, 35: 361-371 (1988).

 Terfenadine may also be useful in treating motion sickness and dizziness. Some antihistamines have been found to be effective in preventing and treating motion sickness. See Wood, Drugs, 17: 471 - 479 (1979). It has also been confirmed that some antihistamines are useful for treating vestibular disorders such as Meniere's disease and other types of dizziness. See Cohen et al, Archives of Neurology, 27: 129-135 (1972).

 In addition, terfenadine may be useful in the treatment of diabetic retinopathy and other small-vascular disorders associated with diabetes mellitus (diabetes mellitus). When tested in rats in which diabetes is induced by streptozocin, antihistamine treatment prevents the activation of retinal histamine receptors, which are involved in the development of diabetic retinopathy. The use of antihistamines for the treatment of retinopathy and small vascular disorders associated with diabetes is disclosed in US Pat. No. 5,019,591.

 It is also believed that terfenadine in combination with non-steroidal anti-inflammatory drugs or other non-narcotic analgesics will be useful in the treatment of cough, colds, colds and / or flu-like symptoms and malaise, pain, headache, fever and general malaise associated with such disorders. The use of pharmaceutical compositions containing terfenadine and non-narcotic analgesics or non-steroidal anti-inflammatory drugs such as aspirin, acetaminophen and ibuprofen are described in US Pat. Nos. 4,783,465 and 4,829,064. Such compositions for treating the symptoms described above may optionally include one or more other active ingredients, including decongestants agents (such as pseudoephedrine), cough suppressants or antitussives (such as dextromethorphan) or expectorants (such as guaifen ezin).

 Many antihistamines cause actions similar to some extent to side effects. Such side effects include, but are not limited to, sedation, gastrointestinal upset, dry mouth, and constipation or diarrhea. Terfenadine has been found to cause relatively less sedation, gastrointestinal upsets, dry mouth and constipation or diarrhea compared to other antihistamines.

 However, it has been found that administration of terfenadine to humans causes other side effects. Such side effects include, but are not limited to, cardiac arrhythmias, including ventricular tachyarrhythmia, flutter-fibrillation, and ventricular fibrillation. Recently, medical practitioners in clinics have noted an increase in the incidence of such cardiac arrhythmias with the joint administration of terfenadine with other drugs, such as ketoconazole and erythromycin, or with an overdose of terfenadine. See Brian P. Monahan et al., In JAMA, 5th Dec 1990, Vol. 264, No. 21, pp. 2788-2790, and the work of Sandra Knowles in the Canadian Journal of Hospital Phasmacy-Vol. 45, No. 1, Ist Feb 1992, p. 33.

 Thus, it would be especially desirable to find a compound with the advantages of terfenadine, but which would not have the aforementioned disadvantages.

 It has now been found that methyl 4- [1-hydroxy-4- (4-hydroxydiphenylmethyl-1-piperidinyl) butyl] -α, α-dimethylbenzene acetate, 4- [1-hydroxy-4- (4-hydroxydiphenylmethyl- 1-pipyridinyl) butyl] -α, α-dimethylbenzene acetic acid and 1- [p- (2-hydroxymethylprop-2-yl) phenyl] -4- [4- (α-hydroxy-α-phenylbenzyl) piperidin-1-yl ] butanol and their optically pure isomers (hereinafter referred to as "metabolic derivatives of terfenadine" and "optically pure isomers of metabolic derivatives of terfenadine") are effective antihistamines. It was also found that pharmaceutical compositions containing metabolic derivatives of terfenadine or their optically pure isomers are suitable for the treatment of allergic diseases and other such conditions, as they can be attributed to compositions with antihistamine activity, and these include, but are not limited to , allergic rhinitis, solar urticaria, and symptomatic darmographism.

 In addition, it has now been found that the metabolic derivatives of terfenadine and their optically pure isomers are useful in the treatment of motion sickness and dizziness, and in the treatment of disorders such as retinopathy and small vascular disorders associated with diabetes mellitus. The present invention also includes methods of treating the conditions described above in humans, while avoiding the side effects that accompany terfenadine, including, but not limited to, cardiac arrhythmia, sedation, gastrointestinal upset, dry mouth and constipation or diarrhea, by introducing metabolic derivatives of terfenadine or their optically pure isomers to said person.

 It was also found that the metabolic derivatives of terfenadine and their optically pure isomers in combination with non-steroidal anti-inflammatory drugs or other non-narcotic analgesics are suitable for the treatment of cough, colds, colds and / or flu-like symptoms and malaise, pain, headache, fever and general malaise, associated with such conditions. Used pharmaceutical compositions of the present invention containing (1) metabolic derivatives of terfenadine or their optically pure isomers and (2) non-narcotic analgesics or non-steroidal anti-inflammatory drugs, such as aspirin, acetaminophen or ibuprofen, may optionally contain one or more other active compounds, including decongestants (such as pseudoephedrine), cough suppressants or cough suppressants (such as dextromethorphan), or expectorants (such as guaia enezin).

 The present invention includes a method of treating a person suffering from or susceptible to an allergic disease, while avoiding interfering side effects associated with the administration of terfenadine, and said method comprises administering to said person suffering from or susceptible to an allergic disease, an amount of one or more compounds, selected from the group consisting of metabolic derivatives of terfenadine, optically pure isomers of metabolic derivatives of terfenadine, and pharmaceutically acceptable salts, said amount being sufficient to treat said allergic disorder but insufficient to cause adverse effects associated with terfenadine.

(I)
в которой Z представляет собой COOH, COOCH₃ или CH₂OH или его фармацевтически приемлемую соль, для применения при антигистаминным лечении, которое не вызывает никакой заметной сердечной аритмии, и такое лечение включает введение пациенту терапевтически эффективного количества соединения формулы I. Соединения формулы I включают метаболические производные терфенадина и их оптически чистые изомеры, о которые упоминается выше.Accordingly, and in its first aspect, the present invention provides a pharmaceutical composition comprising a compound of formula I

(I)
in which Z is COOH, COOCH ₃ or CH ₂ OH, or a pharmaceutically acceptable salt thereof, for use in antihistamine treatment that does not cause any noticeable cardiac arrhythmia, and such treatment comprises administering to the patient a therapeutically effective amount of a compound of formula I. Compounds of formula I include metabolic derivatives of terfenadine and their optically pure isomers, as mentioned above.

 Prior to the present invention, those skilled in the art have believed that compounds of formula I induce a form of cardiac arrhythmia known as flutter-flicker (as reported by Brian P. Monahan et al., In JAMA 5 th Dec 1990. Vol, 264, N 21, pp 2788-2790, and Sandra Knowles in The Canadian Journal of Hospital Pharmacy, Vol. 45, No. 1, ISt Feb 1992, p. 33), since such potentially lethal arrhythmia is considered to be a “group effect” of non-sedative antihistamines, in the sense that the occurrence of arrhythmia is believed to be associated with the antihistamine activity of such compounds. Accordingly, the fact that the composition of the present invention does not cause any such cardiac arrhythmia is a new and very useful and unexpected technical effect, which makes it possible to administer the composition of the invention to individuals sensitive to cardiac arrhythmia, and in potentially higher doses than doses of non-sedative antihistamines, such as terfenadine, which are currently used.

 Antihistamine treatment may be a method of treating a person suffering from or sensitive to an allergic disorder; motion sickness; dizziness retinopathy or other small blood vessel disease associated with diabetes; cough, cold, cold, or flu-like symptoms; or malaise, pain, fever, or general malaise associated with such conditions. In embodiments, the invention may relate to any one, any combination, or all of the above treatments.

 Preferably, the invention relates to the treatment of an allergic disease, which is preferably asthma or allergic rhinitis.

 In preferred embodiments, the antihistamine treatment comprises administering a compound of formula I in an amount of 1-500 mg per day, preferably in an amount of 20-200 mg per day. When the composition of the invention is intended for use in the treatment of asthma or retinopathy, or other small vessel disease associated with diabetes mellitus, a sufficient amount of the composition of the invention should be such that the patient receives a compound of formula I in an amount of 0.01-500 mg per day preferably in an amount of 0.1 to 200 mg per day.

 In preferred embodiments, the composition of the invention also includes a pharmaceutically acceptable carrier or excipient.

 In particular, when antihistamine treatment is a method of treating a person for cough, cold, cold-like or flu-like symptoms or malaise, pain, fever or general malaise associated with such conditions, the composition may also contain a therapeutically effective amount of a non-steroidal anti-inflammatory agent or non-narcotic analgesic, such as acetylsalicylic acid, acetaminophen, ibuprofan, ketoprofen or naproxen, or a pharmaceutically acceptable salt thereof. On the other hand, or in addition, the composition of the present invention may also include a therapeutically effective amount of a decongestant, such as pseudoephedrine, or a pharmaceutically acceptable salt thereof.

 In a preferred embodiment, the composition of the invention comprises from 20 to 200 mg of the compound of formula I and from 25 to 600 mg of an anti-inflammatory agent or analgesic. When the composition of the invention contains a therapeutically effective amount of a decongestant, it preferably contains from 20 to 200 mg of a compound of formula I and from 5 to 150 mg of a decongestant.

 In preferred embodiments of the present invention, the compound of formula I is in the form of only one optical isomer, and the composition essentially does not contain another isomer of such a compound. In such an embodiment of the invention, the compounds of formula I are preferably selected from the group consisting of methyl R - (+) - 4- [1-hydroxy-4- (4-hydroxydiphenylmethyl-1-piperidinyl) butyl] -α, α- dimethylbenzene acetate, R - (+) - 4- [1-hydroxy-4- (4-hydroxydiphenylmethyl-1-piperidinyl) butyl] -α, α-dimethylbenzeneacetic acid and R - (+) - 1- [p- (2- hydroxymethylprop-2-yl) phenyl] -4- [4- (α-hydroxy-α-phenylbenzyl) piperidin-1-yl] butanol and their pharmaceutically acceptable salts, and the composition essentially does not contain the S-stereoisomer of the selected compound ; or the compounds of formula I are selected from the group consisting of methyl-S - (-) - 4- [1-hydroxy-4- (4-hydroxydiphenylmethyl-1-piperidinyl) butyl] -α, α-dimethylbenzeneacetate, S - (-) -4- [1-hydroxy-4- (4-hydroxydiphenylmethyl-1-piperidinyl) butyl] -α, α-dimethylbenzeneacetic acid and S - (-) - 1- [p- (2-hydroxymethylprop-2-yl) phenyl ] -4- (α-hydroxy-α-phenylbenzyl) piperidin-1-yl] butanol and their pharmaceutically acceptable salts, and the composition essentially does not contain the R-stereoisomer of the selected compound.

 The compounds of formula I preferably contain 90% or more of the selected R- or S-stereoisomer.

 In a most preferred embodiment, Z in formula I is COOH, and the compound of formula I is terfenadine carboxylate.

 In another aspect of the present invention, there is provided a method for providing a sick person with an antihistamine treatment that does not cause any noticeable cardiac arrhythmia, and which comprises administering to the sick person a therapeutically effective amount of a pharmaceutical composition according to the first aspect of the invention, preferably one of its preferred variants implementation. Preferably, the method of the invention is a method of treating a person suffering from or susceptible to an allergic disease; motion sickness; dizziness retinopathy; or other small blood vessel disease associated with diabetes; cough, cold, cold, or flu-like symptoms; or malaise, pain, fever, or general malaise associated with such conditions. Preferably, the method is a method of treating a person suffering from or susceptible to an allergic disease, and more preferably, when the allergic disease is asthma or allergic rhinitis.

 In a third aspect, the present invention relates to the use of a composition according to the first aspect of the invention, or to any of its preferred embodiments, in the manufacture of a medicament for use in antihistamine treatment that does not cause any noticeable cardiac arrhythmia, and comprises administering to a sick person a therapeutically effective amounts of a compound of formula I. Preferably, when such use is intended to produce a medicament for use I was at the treatment of humans suffering from or susceptible to an allergic disorder; motion sickness; dizziness retinopathy or other small blood vessel disease associated with diabetes; cough, cold, cold, or flu-like symptoms; or malaise, pain, fever, or general malaise associated with such conditions. Preferably, said method is a method of treating a person suffering from or susceptible to an allergic disease, which is preferably asthma or allergic rhinitis.

 Terfenadine has antihistamine activity and provides treatment and elimination of symptoms of various conditions and disorders related to allergic diseases, diabetes mellitus and other conditions; however, this drug, although giving hope for efficacy, has an undesirable effect. The use of metabolic derivatives of terfenadine or their substantially pure optical isomers results in a clearer, dose-dependent identification of efficacy, reduces side effects and improves the therapeutic index. Therefore, it is preferable to use the metabolic derivative of terfenadine or its optically pure isomer than terfenadine itself.

 The term “side effect” (“undesirable effect”) includes, but is not limited to, cardiac arrhythmia, sedation, gastrointestinal upset, dry mouth, constipation and diarrhea. The term "cardiac arrhythmia" includes, but is not limited to, ventricular tachyarrhythmia, flutter-fibrillation, and ventricular fibrillation.

 The term “substantially free of the S-stereoisomer,” as used, means that the metabolic derivative of terfenadine present in the composition contains at least 90 wt.% The R-isomer of the metabolic derivative of terfenadine and 10 wt.% Or less of the S-derivative . In a preferred embodiment, the term “substantially free of the S-stereoisomer” means that the metabolic derivative of terfenadine in the composition contains at least 90% by weight of the R-isomer of the metabolic derivative of terfenadine and 1% or less of the S-isomer. In another preferred embodiment, the term “substantially free of the S-stereoisomer,” as used herein, means that the metabolic derivative of terfenadine in the composition contains more than 99% by weight of the R-isomer of the metabolic derivative of terfenadine and less than 1% by weight of S- derivative. The terms “substantially optically pure R-isomers of metabolic derivatives of terfenadine” and “optically pure R-isomers of metabolic derivatives of terfenadine” are also encompassed by the above definitions.

 The term “substantially free of the R stereoisomer,” as used herein, means that the composition contains at least 90 wt.% S-isomers of the metabolic derivatives of terfenadine and 10 wt.% Or less of R-derivatives. In a preferred embodiment, the term “substantially free of R-stereoisomer” means that the composition contains at least 99 weight. % S-isomers of the metabolic derivatives of terfenadine and 1% or less of the R-isomers. In another preferred embodiment, the term “substantially free of the R stereoisomer,” as used herein, means that the composition contains more than 99 wt.% S-isomers of metabolic derivatives of terfenadine and less than 1 wt.% R-derivatives. These percentages refer to the total amount of metabolic derivatives of terfenadine in the composition. The terms “substantially optically pure S-isomers of metabolic derivatives of terfenadine” and “optically pure S-isomers of metabolic derivatives of terfenadine” are also encompassed by the above definitions.

 The phrase "therapeutically effective amount" means an amount of one or more compounds of the invention that provides a beneficial therapeutic effect in antihistamine treatment, including treatment or care for allergic diseases, asthma, retinopathy or other diseases of the small vessels associated with diabetes mellitus, motion sickness, dizziness, or coughing, colds, colds and / or flu-like symptoms and malaise, pain, fever and general malaise associated with these conditions. Examples of allergic diseases include, but are not limited to, allergic rhinitis, solar urticaria, and symptomatic dermographism. Symptoms associated with these allergic diseases, coughs, colds, colds and / or flu-like symptoms include, but are not limited to, sneezing, rhinorrhea, lacrimation, and painful skin sensitivity. The term "asthma" defines a disease characterized by an increased susceptibility of the trachea and bronchi to various stimuli, which appears in symptoms that include steroid breathing, coughing and shortness of breath. The term "dizziness", as used here, means dizziness associated with movement, height, change in body position, but is not limited to this. The term "diabetic retinopathy", or "diabetes mellitus-related retinopathy" refers to a disease caused by increased permeability of the capillaries of the eye, which leads to hemorrhage and swelling of the eye and can lead to blindness. The term "small vessel diseases associated with diabetes mellitus" includes, but is not limited to, diabetic retinopathy and peripheral vascular disease.

 Separation of optically pure isomers of the metabolic derivatives of terfenadine can be carried out by cleavage of the racemic mixture of enantiomers of the metabolic derivatives of terfenadine using conventional means, such as optically active cleaving acid. In addition, optically pure isomers of the metabolic derivatives of terfenadine can be obtained from the racemic mixture by enzymatic biocatalytic cleavage. See, for example, US patents NN 5057427 and 5077217, the descriptions of which are incorporated into this invention by reference.

 The value of the prophylactic or therapeutic dose of the metabolic derivative of terfenadine or its optically pure isomer during emergency therapy or long-term treatment of the disease will vary depending on the severity of the condition being treated and the route of administration. The dose, and possibly the frequency of the dose, will also vary in accordance with the age, body weight and individual response of the patient. In general, the total daily dose interval for the conditions described herein is from 0.01 to 50 mg, which are administered as a single dose or in divided doses orally, topically, transdermally or locally using an aerosol. For example, the preferred daily dosage interval for oral administration should be from 1 to 500 mg, while the most preferred daily dosage interval for oral administration should be from 20 to 200 mg. In addition, it is recommended that children, patients over 65 years of age, and patients who have impaired renal or hepatic function, first give small doses, which are then titrated (adjusted) based on an individual reaction (s) or blood levels. In some cases, it may be necessary to apply doses that go beyond the specified limits, which will be obvious to specialists. We also note that it will be clear to the doctor in the clinic or to the attending physician when and how to interrupt, adjust or end the treatment, depending on the individual patient response.

 Various terms, such as "an amount sufficient to alleviate an allergic disease, but not enough to cause the mentioned side effects," "an amount sufficient to alleviate the aforementioned asthma, but not enough to cause the said undesirable effects," "an amount sufficient to alleviate said motion sickness, but not enough to cause said undesirable actions "and" an amount sufficient to alleviate said retinopathy and other small vessel diseases associated with diabetes mellitus, but not sufficient to cause the mentioned side effects, "are covered by the above dosages and the regimen of their administration. In addition, the expression "pharmaceutical composition for use in treating a person with cough, cold, cold-like and / or flu-like symptoms and malaise, pain, fever and general malaise associated with these conditions, said composition containing (i) a therapeutically effective amount of at least at least one metabolic derivative of terfenadine or an optically pure isomer thereof, with (ii) a therapeutically effective amount of at least one non-steroidal anti-inflammatory agent or non-narcotic otic analgesic "and the expression" a pharmaceutical composition for use in treating a person with cough, cold, colds and / or flu-like symptoms and malaise, pain, headache, fever and general malaise associated with these conditions, said composition comprising (i) therapeutically an effective amount of at least one metabolic derivative of terfenadine or an optically pure isomer thereof, with (ii) a therapeutically effective amount of a decongestant, "as well as the expression" those apevticheski effective amount of at least one derivative of α- aryl-4-substituted piperidinoalkanol derivative "are also encompassed by the above-described dosages and schemes of their application.

 Any suitable route of administration may be used to provide the patient with an effective dose of the composition of the invention. For example, oral, rectal, parenteral, transdermal, subcutaneous, intramuscular and the like administration forms can be used. Dosage forms include tablets, lozenges, dispersions, suspensions, solutions, capsules, pads and the like.

 The pharmaceutical compositions of the present invention contain, as an active ingredient, a metabolic derivative of terfenadine or an optically pure isomer thereof or pharmaceutically acceptable salts thereof, and may also include a pharmaceutically acceptable carrier and, optionally, other therapeutic ingredients.

 The term "pharmaceutically acceptable salts" includes salts derived from pharmaceutically acceptable non-toxic acids or bases, including inorganic acids or bases, or organic acids or bases. Examples of such inorganic acids are hydrochloric acid, hydrobromic, hydroiodic, sulfuric and phosphoric acids. Suitable organic acids can be selected, for example, from aliphatic, aromatic, carboxylic and sulfonic organic acids, examples of which are formic, acetic, propionic, succinic, glycolic, glucoronic, maleic, furoic, glutamic, benzoic, anthranilic, salinicyl , embonic (pamova), methanesulfonic, ethanesulfonic, pantothenic, benzenesulfonic, stearic, sulfanilic, alginic and galacturonic acids. Examples of such inorganic bases are metal salts, which include aluminum, calcium, lithium, magnesium, potassium, sodium and zinc. Suitable organic bases may be selected, for example, from N, N'-dibenzylethylenediamine, chlorprocaine, choline, diethanolamine, ethylenediamine, meglumain (N-methylglucamine), lysine and procaine.

 The composition of the present invention includes compositions such as suspensions, solutions and elixirs; or carriers, such as starches, sugars, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrating agents, and the like, in the case of solid preparations (such as powders, capsules and tablets) for oral administration, moreover, solid preparations for oral administration are preferred over liquid preparations for oral administration. The most preferred solid preparations for oral administration are tablets.

 Because of their ease in administration, tablets and capsules represent the most convenient dosage unit form for oral administration, in which case solid pharmaceutical carriers are used. If desired, tablets may be coated with standard techniques, with or without water.

 In addition to the conventional dosage forms mentioned above, the compounds of the present invention can also be administered by controlled release agents and / or delivery devices, such as the devices described in US Pat. Nos. 3,845,770, 3,916,899, 3,536,809, 3,598,123 and 4,087,919.

 Pharmaceutical compositions of the present invention suitable for oral administration can be presented in discrete units, such as capsules, cachets, or tablets, or aerosol containers, each of which contains a predetermined amount of the active ingredient, in the form of powder or granules, or in the form of a solution or suspension in an aqueous liquid, in a non-aqueous liquid, an oil-in-water emulsion or a water-in-oil emulsion. Such compositions may be prepared by any method known in the art of pharmacy, but all methods include the step of bringing into association the active ingredient with a carrier that consists of one or more necessary ingredients. In general, compositions are prepared by thoroughly mixing the active ingredient to a homogeneous state with liquid carriers, or finely divided solid carriers, or both, and then, if necessary, forming the product into the desired shape.

 For example, tablets may be prepared by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free-flowing form, such as a powder or granules, optionally mixed with a binder, lubricant, inert diluent, surfactant or dispersant. Molded tablets may be made in a suitable machine by molding a mixture of the powdered compound moistened with an inert liquid diluent. Preferably, each tablet contains from 10 to 150 mg of the active ingredient, and each cachet or capsule contains from 10 to 150 mg of the active ingredient, i.e. metabolic derivative of terfenadine. Most preferably, the tablet, cachet, or capsule contains one of the three indicated doses — 30, 60, or 90 mg — of the active ingredient.

 The invention is further defined by examples describing in detail the preparation of the compounds and compositions of the present invention, as well as their use. It will be apparent to those skilled in the art that in practice numerous modifications of both materials and methods can be made that are within the scope of the present invention.

Examples
Example 1
A. Preparation of methyl R-4- [1-hydroxy-4- (4-hydroxydiphenylmethyl-1-piperidinyl) butyl] -α, α-dimethylbenzene acetate
4- (α-hydroxy-α-phenylbenzyl) piperidine (4.3 g) is combined with methyl p- (4-chloro-1-oxobutyl) -α, α-dimethylbenzene acetate (4.5 g), potassium bicarbonate (2 9 g), potassium iodide (approximately 50 mg) and methyl isobutyl ketone (50 ml), and heated under reflux for 48 hours. An additional amount of 4- (α-hydroxy-α-phenylbenzyl) piperidine (1.1 g) was added and heating was continued for an additional 48 hours. After the mixture was cooled to room temperature, water was added and the pH of the solution was adjusted to approximately 12 by adding an aqueous solution of sodium hydroxide. The mixture was extracted with ethyl acetate. The ethyl acetate solution was washed with saturated aqueous sodium bicarbonate and brine, and dried over sodium sulfate. Ethyl acetate was removed on a rotary evaporator, and the residue was treated with 25% ethyl acetate in hexane. The resulting precipitate was filtered off and dried in air to give methyl 4- [oxo-4- (4-hydroxydiphenylmethyl-1-piperidinyl) butyl] -α, α-dimethylbenzene acetate. This intermediate precipitate (2.4 g) was combined with tetrahydrofuran (10 ml) and (+) - β-chloro-diisopinocamphenylborane (4.5 g) and stirred for 48 hours. Methanol (10 ml) and sodium bicarbonate (1.5 g) were added to the reaction solution, and the mixture was stirred for 12 hours. The mixture was diluted with ethyl acetate (200 ml), washed with saturated aqueous sodium bicarbonate, and methyl-R-4 [1-hydroxy-4- (4-hydroxydiphenylmethyl-1-piperidinyl) butyl] -α, α-dimethylbenzene acetate was obtained.

диметилбензолацетат (1,2 г) с гидроксидом калия (0,4 г) и этанолом (5 мл) и смесь нагревают с обратным холодильником в течение 7 часов. Этанол удаляют на роторном испарителе и остаток растворяют в воде (2 мл). Водный раствор подкисляют ледяной уксусной кислотой для получения твердого вещества, которое перекристаллизовывают из смеси метанола с этилацетатом (1: 1), и получают R-4-[1-гидрокси-4-(4-гидроксидифенилиметил-1-пиперидинил)бутил] -α,α- диметилбензолуксусную кислоту (R-терфенадинкарбоксилат) (т.пл. 213 - 215^oC).B. R - (+) - 4- [1-Hydroxy-4- (4-hydroxydiphenylmethyl-1-piperidinyl) butyl [-α, α-dimethylbenzeneacetic acid [R - (+) - terfenadinecarboxylate]
Connect methyl R-4- [1-hydroxy-4- (4-hydroxydiphenylmethyl-1-piperidinyl) butyl]

dimethylbenzene acetate (1.2 g) with potassium hydroxide (0.4 g) and ethanol (5 ml) and the mixture was heated under reflux for 7 hours. Ethanol was removed on a rotary evaporator and the residue was dissolved in water (2 ml). The aqueous solution was acidified with glacial acetic acid to obtain a solid which was recrystallized from a mixture of methanol and ethyl acetate (1: 1) to give R-4- [1-hydroxy-4- (4-hydroxydiphenylmethyl-1-piperidinyl) butyl] -α , α-dimethylbenzeneacetic acid (R-terfenadinecarboxylate) (mp 213 - 215 ^° C).

C. Preparation of methyl S-4- [1-hydroxy-4- (4-hydroxydiphenylmethyl-1-piperidinyl) butyl] -α, α-dimethylbenzene acetate
4- (α-hydroxy-α-phenylbenzyl) piperidine (4.3 g) is mixed with methyl p- (4-chloro-1-oxobutyl) -α, α-dimethylbenzene acetate (4.5 g), potassium bicarbonate (2 9 g), potassium iodide (approximately 50 mg) and methyl isobutyl ketone (50 ml) and heated under reflux for 48 hours. An additional amount of 4- (α-hydroxy-α-phenylbenzyl) piperidine (1.1 g) was added and heating was continued for an additional 48 hours. After the mixture was cooled to room temperature, water was added and the pH of the solution was adjusted to approximately 12 by adding an aqueous solution of sodium hydroxide. The mixture was extracted with ethyl acetate. The ethyl acetate solution was washed with saturated aqueous sodium bicarbonate with brine and dried over sodium sulfate. Ethyl acetate was removed on a rotary evaporator and the residue was taken up in 25% ethyl acetate in hexane. The resulting precipitate is filtered off and dried in air. Methyl 4- [1-oxo-4- (4-hydroxydiphenylmethyl-1-piperidinyl) butyl] -α, α-dimethylbenzene acetate is obtained. This precipitate of intermediate (2.4 g) was mixed with tetrahydrofuran (10 ml) and (-) - β-chlorodiisopinocamphenylborane (4.5 g) and stirred for 48 hours. Methanol (10 ml) and sodium bicarbonate (1.5 g) were added to the reaction solution, and the mixture was stirred for 12 hours. The mixture was diluted with ethyl acetate (200 ml) and washed with saturated aqueous sodium bicarbonate to give methyl-S-4- [1-hydroxy-4- (4-hydroxydiphenylmethyl-1-piperidinyl) butyl] -α, α-dimethylbenzene acetate. If the above-mentioned precipitate of the intermediate is reacted with racemic β-chlorodiisopinocamphenylborane, then a racemic mixture of methyl 4- [1-hydroxy-4- (4-hydroxydiphenylmethyl-1-piperidinyl) butyl] -α, α-dimethylbenzene acetate will be obtained.

DS - (-) - 4- [1-Hydroxy-4- (4-hydroxydiphenylmethyl-1-piperidinyl) butyl] -α, α-dimethylbenzeneacetic acid
[S - (-) - terphenidinecarboxylate]
Methyl S-4- [1-hydroxy-4- (4-hydroxydiphenylmethyl-1-piperidinyl) butyl] -α, α-dimethylbenzene acetate (1.2 g) is mixed with potassium hydroxide (0.4 g) and ethanol (5 ml) and the mixture is heated under reflux for 7 hours. Ethanol was removed on a rotary evaporator and the residue was dissolved in water (2 ml). The aqueous solution was acidified with glacial acetic acid to obtain a solid which was recrystallized from a mixture of methanol and ethyl acetate (1: 1) to obtain S - (-) - 4- [1-hydroxy-4- (4-hydroxydiphenylmethyl-1-piperidinyl) butyl] -α, α-dimethylbenzeneacetic acid (S-terfenadinecarboxylate) (mp 215 - 218 ^° C).

Example 2
The histamine H ₁ receptor activity of the compounds of the invention was evaluated using the definition of [ ³ H] pyrilamine binding as described by Chang et al., J. Neurochem, 32; 1653 - 1663 (1979). Briefly, the test is carried out as follows. Membranes from the cerebellum of the cow are incubated with [ ³ H] -pyrilamine and varying concentrations of the test compound. The reaction is carried out in 50 mm sodium phosphate buffer (pH 7.5) at 25 ^o C for 30 minutes. The reaction is terminated by rapid filtration under vacuum through fiberglass filters. The radioactivity trapped in the filters is determined and compared with control values to verify the interaction of the test compound with the H ₁ receptor. The following results are obtained (see table. 1).

Example 3
Separate ventricular myocytes are obtained from isolated cat hearts by conventional techniques. Rod-shaped individual cells are stored in a HEPES buffer and are "fixed in patch clamps" using pipettes calibrated to the suction volume. To record current curves, a Patch-Clamp L / M-PEC 7 amplifier is used and the recording electrodes are filled with potassium aspartate solution. Heap voltage pulses (Clamp) and information are controlled by a Sperry PC / IT computer, looking at soft “patch” formations (P Clamp software). A minimum of 4 cells was examined at each experimental concentration of the following drugs: racemic terfenadine, racemic terfenadine carboxylate and quinidine (as the compound selected for comparison). The results are given below (see table. 2).

 These results show that, surprisingly, terfenadine carboxylate is not prone to cause cardiac arrhythmia at dose levels at which there is a clear risk of such side effects caused by terfenadine itself.

 The active ingredient, which may be instead of (S) terfenadine carboxylate (R) terfenadine carboxylate or racemic terfenadine carboxylate, is sieved and mixed with excipients. The mixture is poured into a suitable size of two-part hard gelatine capsules using suitable mechanisms. You can prepare other doses by changing the fill weight, and, if necessary, changing the size of the capsule to a suitable one.

Example 5
The oral formulation is tablets (see tab. 4).

 The active ingredient, which may be instead of (R) -terfenadine carboxylate or (S) -terfenadine carboxylate or racemic terfenadine carboxylate, is sieved and mixed with lactose until a homogeneous mixture is formed. An appropriate volume of water is added and the powders are granulated. After drying, the granules are sieved and mixed with magnesium stearate. The resulting granules are compressed into tablets of the desired shape. Tablets with different efficacy can be obtained by changing the ratio of active ingredient to excipient (s) or compression mass.

Claims (20)

1. A pharmaceutical composition comprising a metabolite of terfenadine of the formula

or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or excipient for the treatment of allergic rhinitis that does not cause cardiac arrhythmia, characterized in that it contains 15 to 90 wt.% terfenadine metabolite in the form of the R - (+) - stereoisomer, essentially free of S - (-) - isomer, and 85-10% by weight of a pharmaceutically acceptable carrier or excipient.  2. The pharmaceutical composition according to claim 1, characterized in that it additionally contains about 25 to 600 mg of a non-steroidal anti-inflammatory drug or non-narcotic analgesic.  3. The pharmaceutical composition according to claim 2, characterized in that it contains about 50 to 300 mg of an anti-inflammatory agent or analgesic.  4. The pharmaceutical composition according to claim 1, characterized in that it additionally contains about 5 to 150 mg of decongestant or decongestant.  5. The pharmaceutical composition according to claim 4, characterized in that it contains about 10 to 75 mg of decongestant or decongestant. 6. A pharmaceutical composition comprising a metabolite of terfenadine of the formula

or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or excipient for the treatment of allergic rhinitis that does not cause cardiac arrhythmias, characterized in that it contains 15 to 90 wt.% terfenadine metabolite in the form of S - (-) - stereoisomer, essentially free of R - (+) - isomer, and 85 - 10 wt.% Pharmaceutically acceptable carrier or excipient.  7. The pharmaceutical composition according to claim 6, characterized in that it additionally contains about 25 to 600 mg of a non-steroidal anti-inflammatory agent or non-narcotic analgesic.  8. The pharmaceutical composition according to claim 7, characterized in that it contains about 50 to 300 mg of an anti-inflammatory agent or analgesic.  9. The pharmaceutical composition according to claim 6, characterized in that it further comprises about 5 to 150 mg of decongestant or decongestant.  10. The pharmaceutical composition according to claim 9, characterized in that it contains about 10 to 75 mg of decongestant or decongestant. 11. A pharmaceutical composition comprising a compound of formula I

or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or excipient for treating allergic rhinitis that does not cause cardiac arrhythmia, characterized in that it contains 15 to 90 wt.% a terfenadine metabolite of the formula I and 85 to 10 wt.% of a pharmaceutically acceptable carrier or excipient .  12. The pharmaceutical composition according to claim 11, characterized in that it further comprises about 25 to 600 mg of a non-steroidal anti-inflammatory agent or non-narcotic analgesic.  13. The pharmaceutical composition according to p. 12, characterized in that it contains about 50 to 300 mg of an anti-inflammatory agent or analgesic.  14. The pharmaceutical composition according to claim 11, characterized in that it further comprises about 5 to 150 mg of decongestant or decongestant.  15. The pharmaceutical composition according to 14, characterized in that it contains about 10 to 75 mg of decongestant or decongestant. 16. A pharmaceutical composition in the form of an oral solid preparation comprising 60 mg of a compound of the formula

or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or excipient for the treatment of allergic rhinitis that does not cause cardiac arrhythmia.  17. The pharmaceutical composition according to clause 16, characterized in that it further comprises an effective amount of a non-steroidal anti-inflammatory agent or non-narcotic analgesic.  18. The pharmaceutical composition according to clause 16, characterized in that it contains about 25 to 600 mg of anti-inflammatory drugs or analgesics.  19. The pharmaceutical composition according to any one of paragraphs.16 to 18, characterized in that it further comprises an effective amount of decongestant or decongestant.  20. The pharmaceutical composition according to claim 19, characterized in that it contains about 5 to 150 mg of decongestant or decongestant.

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